Airway Obstruction
Airway obstruction caused by inflammatory exudation is a major cause of morbidity and mortality. Mucus plugging and stasis is a feature of chronic bronchitis, asthmatic bronchitis, bacterial bronchopneumonia and, especially, cystic fibrosis, and is associated with destruction of lung substance. Mucus also contributes to the morbidity of acute and chronic sinusitis and even the common cold.
Mucoid obstruction of the respiratory system is multifactorial. One factor is increased mucus synthesis and release caused by inflammatory mediators elicited by infection or irritation. In cystic fibrosis, the viscosity of mucus is increased, presumably because of abnormal epithelial ion transport which affects the hydration or charge of the ionic polymers composing the mucus substance. The thick mucus of cystic fibrosis prevents bacterial clearance by ciliary transport and favors the growth of bacteria, especially Pseudomonas aeruginosa. These bacteria or irritants, such as tobacco smoke generate chemoattractants which recruit leukocytes into the airway. As the leukocytes engage bacteria they degenerate, and their components contribute debris that affect the viscoelasticity of the airway contents.
Much research in the area of pathological mucoid airway contents has focused on DNA, since DNA was originally isolated from pus. However, there has also been research on the mucopolysaccharide composition of mucus and the role of disulfide bonding (Roberts, G. P., Arch. Biochem. Biophys. 173:528-537 (1976); Roberts, G. P., Eur. J. Biochem. 50:265-280 (1974); Charman, J., et al., Brit. J. Dis. Chest 68:215 (1974); Bhaskar, K. R., et al., Exp. Lung Res. 10:401-422 (1986); Lethem, M. I., et al., Eur. Respir. J. 3:19-23 (1990)). Purulent mucus contains about 10-13 mg/ml of DNA, an ionic polymer predicted to affect the rheologic properties of airway fluids. Accordingly, bovine pancreatic DNase I, an enzyme that degrades DNA, was tested as a mucolytic agent many years ago but did not enter clinical practice, because of side effects induced by antigenicity and/or contaminating proteases. Recently, recombinant human DNase I was tested as a therapeutic agent. The cDNA for human. DNase I was cloned and expressed. It was shown to diminish the viscosity of cystic fibrosis mucus in vitro (Shak, S., et at., Proc. Natl. Acad. Sci. USA 87:9188-9192 (1990)). Human DNase I has moved beyond phase I trials and reportedly is effective in improving subjective and possibly objective manifestations of purulent airway disease (Aitken, M., et al., JAMA 267:1947-1951 (1992)).